Aza-bicycloalkyl ethers and their use as alpha7-nAChR agonists

Abstract

The present invention relates to 1-aza-bicycloalkyl derivatives of formula I, wherein X is CH 2 or a single bond; Y is a group of formula and wherein R has the meanings as defined in the specification, which compounds are alpha 7 nicotinic acetylcholine receptor (nAChR) agonists; to processes for their production, their use as pharmaceuticals and to pharmaceutical compositions comprising them.

1. The compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein
 X is CH 2  or a single bond; 
 Y is a group of formula 
 
       
         
           
           
               
               
           
         
       
       and
 R is phenyl, naphthyl, tetrahydronaphthyl, indanyl, thienyl, benzothienyl, furanyl, benzofuranyl and isobenzofuranyl, which in each case can be unsubstituted or mono-, di- or trisubstituted by halogen, cyano, formyl, acetyl, C 1 -C 3 alkoxycarbonyl, N,N-di-(C 1 -C 3 alkyl) carbamoyl, phenyl, phenoxy, methylendioxy, ethylendioxy; or
 C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkinyl or C 1 -C 4 alkoxy, which radicals themselves can be unsubstituted or mono-, di- or trisubstituted by halogen; 
 
 in free base or acid addition salt form. 
 
     
     
       2. The compound of formula I according to  claim 1 , wherein
 X and Y are as defined in  claim 1 , and 
 R is 
 (a) phenyl which is unsubstituted or mono-, di- or trisubstituted by halogen, cyano, methylendioxy,
 C 1 -C 4 alkyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, or 
 C 1 -C 4 alkoxy, which is unsubstituted or mono-, di- or trisubstituted by halogen, 
 
 (b) naphthyl, indanyl, tetralinyl or 
 (c) furanyl, benzofuranyl, isobenzofuranyl, benzothienyl or thienyl, 
 in free base or acid addition salt form. 
 
     
     
       3. The compound of formula I according to  claim 1 , wherein
 X and Y are as defined in  claim 1 , and 
 R is 
 (a) phenyl which is unsubstituted or mono-, di- or trisubstituted by halogen, cyano, methylendioxy,
 C 1 -C 4 alkyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, or 
 C 1 -C 4 alkoxy, which is unsubstituted or mono-, di- or trisubstituted by halogen, 
 
 (b) naphthyl, or 
 (c) furanyl, benzofuranyl, isobenzofuranyl, or thienyl, 
 in free base or acid addition salt form. 
 
     
     
       4. A process for the preparation of the compound of formula I as defined in  claim 1 , or a salt thereof, which comprises the step of reacting a compound of formula II
   z-Y—R  (II) 
 
       wherein Y and R are as defined in  claim 1  and z is a leaving groups, with a compound of formula III 
       
         
           
           
               
               
           
         
       
       wherein X is as defined in  claim 1 ,
 and recovering the so obtained compound of formula I in free base or acid addition salt form. 
 
     
     
       5. A pharmaceutical composition comprising the compound according to  claim 1  in free base or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. 
     
     
       6. A pharmaceutical composition comprising the compound according to  claim 2  in free base or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. 
     
     
       7. A pharmaceutical composition comprising the compound according to  claim 3  in free base or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. 
     
     
       8. The compound of formula I according to  claim 1 , selected from the group consisting of
 (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, 
 (racemic)-3-(5-phenyl-pyridin-2-yloxy)-1-aza-bicyclo[2.2.2]octane, 
 (R)-3-(5-phenyl-pyridin-2-yloxy)-1-aza-bicyclo[2.2.2]octane, 
 (R)-3-(6-phenyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, 
 (R)-3-(6-(3-trifluoromethyl-phenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, 
 (R)-3-(6-(2-chloro-phenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, 
 (R)-3-(6-thiophen-2-yl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, 
 (R)-3-(6-o-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, 
 (R)-3-(6-m-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, 
 (R)-3-(6-(2,3-dimethyl-phenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, 
 (R)-3-(6-(4-ethyl-phenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, 
 (R)-3-(6-(3,4-dimethyl-phenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, 
 (R)-3-(6-(2-chloro-4-methyl-phenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, 
 (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.1]heptane, 
 (R)-3-(6-(1-naphthyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, 
 (R)-3-(6-(2-naphthyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane and 
 (R)-3-(6-(2-chloro-5-methyl-phenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane; in free base or acid addition salt form. 
 
     
     
       9. The compound of formula I according to  claim 1 , selected from the group consisting of
 (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, 
 (R)-3-(6-phenyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, 
 (R)-3-(6-(4-ethyl-phenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, and 
 (R)-3-(6-(3,4-dimethyl-phenyl)-pyridin-3-yloxy)-1-aza-bicyclo [2.2.2]octane; in free base or acid addition salt form. 
 
     
     
       10. The compound (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, in free base or acid addition salt form. 
     
     
       11. The compound (R)-3-(6-phenyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, in free base or acid addition salt form. 
     
     
       12. The compound (R)-3-(6-(4-ethyl-phenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, in free base or acid addition salt form. 
     
     
       13. The compound (R)-3-(6-(3,4-dimethyl-phenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane, in free base or acid addition salt form.